Objective/Hypothesis: Adolescence is a time period notable for significant brain maturation and refinement of neuronal connections, and also for a marked increase in prevalence of Major Depressive Disorder (MDD). Fronto-limbic neural networks mediate emotional processing and are implicated in the pathophysiology of MDD. Our over-arching hypothesis is that MDD results from abnormal development of fronto-limbic neural circuitry. Recent advances in neuroimaging methodology have allowed for measuring the strength of neural connections, or connectivity. For instance, diffusion tensor imaging (DTI) can be used to measure structural connectivity, and resting-state functional magnetic resonance imaging (rsfMRI) can be used to measure functional connectivity. In a preliminary study using these methods in 14 adolescents with MDD and 14 healthy comparison subjects, we identified a reduction in both structural and functional connectivity between the subgenual anterior cingulate cortex and other key fronto-limbic areas in the depressed group. Conclusions from these findings are limited due to confounds related to small sample size and medication exposure in the depressed group. In order to better characterize the developmental abnormalities in fronto-limbic networks in depressed adolescents, we now propose to conduct a multi-modal neuroimaging investigation to examine structural and functional connectivity in a larger, treatment-naive sample. Proposed Methods: 30 adolescents aged 13-17 with familial, adolescent onset, moderate-severe MDD and 30 healthy comparisons matched for sex, handedness, SES and IQ will be recruited from clinical settings at the University of Minnesota and the community. Assessment will include the K-SADS-PL, BDI, CDRS, and WASI. Neuorimaging scans will be obtained at a research-dedicated Siemens 3T scanner at UMN. Structural, diffusion tensor, and resting-state functional images will be collected. Structural connectivity data will be analyzed using a voxel-wise comparison and also using probabilistic tractography. Functional connectivity will be analyzed using a seed-based approach. Discussion/Significance: Demonstration of abnormal connectivity within fronto-limbic neural networks in depressed teens will inform our understanding of the neurodevelopmental mechanisms of adolescent MDD. The dataset from the proposed project will provide the foundation for future longitudinal investigations to (1) delineate trajectories of neural development in individuals with MDD, (2) identify predictors for treatment response, (3) examine the impact of treatment on neural circuitry, and (4) investigate the genetic and environmental underpinnings of abnormal neural development in adolescent MDD. By identifying neurodevelopmental abnormalities that underlie the pediatric depression, our hope is to inform the development of interventions that will alter negative trajectories.